Oxidative and endoplasmic reticulum stress in absence epilepsy

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In order to characterize absence epilepsy-associated increases in endoplasmic reticulum (ER) stress-induced celluar damege in lethargic(Ih/Ih)mice, a genetic model of absence epilepsy, responsible pathways involved in the ER stress-induced cell death in the brain were compared between lethargic and control mice. The wet weight of the thalamus in lethargic mouse was lower than that in control mouse. The thalamus has been shown to play an important role in the absence epilepsy. The level of glucose regulated protein (GRP)78, ER chaperons, and activity of c-jun-N-terminal kinase (JNK), phospho-JNK/JNK in the thalamus of lethargic mouse higher than that of control mouse. These data suggested that ER stress was induced in the thalamus in a model of absence epilepsy.In order to elucidate underlying mechanism of cell injury pathways, ER stress (tunicamycine ; TM)- and oxidative stress (H_2O_2 and 4-hydroxy-2-nonenal ; HNE)-induced cell injury pathways were investigated in HT22 cells, a mouse hippocampal cell line. Treatment with TM, H_2O_2 and HNE decreasedthecell viability in a time-and concentration-dependent manner. GADD153/C/EBP homologous protein (CHOP) was significantly induced after exposure to TM. In contrast, expression of caspase-12, ER stress-specific caspase, was not affected by TM. In the cells treated with H_2O_2, significant increases in the immunoreactivities of DJ-1 and nuclear factor-kB (NF-kB) subunits were observed in the nuclear fraction. H2O2 also induced an increase in the intracellular concentration of Ca^<2+> and cobalt chloride, a Ca^<2+> channel inhibitor, suppressed the H_2O_2-induced cell death. In HNE-treated cells, none of these phenomena were observed ; however, HNE adduct proteins were formed after exposure to HNE, but not to H_2O_2.Further experiments are needed to ascertain whether the details of responsible pathways involved in the ER and oxidative stress in absence epilepsy.